The goal of this proposal is to change this landscape in Trypanosoma cruzi drug development. We propose the development of a consortium of academic laboratories and pharmaceutical companies who will investigate a variety of independently identified drug targets and candidate compounds. Specifically, the development of novel nitrotriazoles, isoprenoid pathway inhibitors, phosphodiesterase inhibitors, protease inhibitors and inhibitors of galactofuranose will be pursued by the academic and industrial partners in this Consortium. Target identification and validation, and compound synthesis will be conducted at multiple sites, relying on the specific expertise of the partners to pursue distinct leads. Screens of compound libraries, or individual candidate molecules, will be conducted centrally using a set of rigorous, well-validated in vitro and in vivo assays. An Advisory Board consisting of the directors of the individual projects in the Consortium, and supplemented with outside experts, will meet twice yearly to assess progress and determine priorities for testing and further development. These meetings will also be opportunities for the development of further collaborations between the academic and industrial partners in the consortium - these types of relationships will be necessary to move beyond the testing we will conduct as part of this study and into further lead optimization, safety and efficacy trials in larger animals, and eventually, humans. Factors such as demonstrated efficacy in initial tests, therapeutic index, ease of synthesis, availability of derivative libraries, and demonstrated safety or prior licensing for use in humans will determine which candidates will move forward in the testing pipeline and which will be dropped. Additionally, the Consortium will entertain applications for additional partners with candidate compounds against targets that are judged to be highly druggable. Combination therapies- delivering multiple newly identified compounds directed at distinct targets or a combination of new compounds with compounds currently in use will be investigated to identify drug combinations which are effective using shorter treatment periods or lower doses. Chagas disease, the result of infection with the protozoan Trypanosoma cruzi, has been described as one of the "most neglected of the neglected diseases", affecting up to 20 million individuals in the Americas. The focus of this proposal is the discovery and development of drugs to treat this infection.